The recent discovery of chronic wasting disease in cervids (CWD) beyond theborders of Colorado and Wyoming, as far east as New York and including twoCanadian Provinces, has led to the emergence of CWD as a prion disease ofdomestic and international importance. The apparent ease of horizontaltransmission, potentially via environmental contamination or byprion-containing saliva, creates enormous challenges for disease management.Ongoing studies of CWD interspecies transmission by exposure of domestic andnon-domestic species directly or using transgenic mice have shed light onspecies barriers. Transgenic mice expressing cervid PrP have also provenuseful for assessing the genetic influences of Prnp polymorphisms on CWDsusceptibility. Accumulating evidence of CWD pathogenesis indicates that themisfolded prion protein, PrPSc, seems to be widely disseminated in manynonneural organs, and CWD infectivity has been recently detected in blood.This review highlights recent research findings in this disease offree-ranging wildlife.

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3. CWD prion spread and target organs

Collectively, CWD pathogenesis studies have revealed extensive deposition ofPrPSc in thecentral nervous system (CNS) and extraneural tissues (Fig. 1). The onlyother natural priondiseases that even approach this degree of systemic involvement are variantCreutzfeldt-Jakob disease (vCJD) in humans, sheep scrapie, and transmissible minkencephalopathy[22, 23, 30, 61, 62]. In mule deer, PrPSc is detectable in theretropharyngeal lymph nodewithin only 6 weeks following an oral exposure [76]. In a further study ofthe kinetics of prion1 http://www.aphis.usda.gov/vs/nahps/cwd/cwd-distribution.html

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infection in mule deer, Fox et al. showed that PrPSc is widely distributedin lymphoid tissuesby 3 months post-oral exposure when it is first detected in brain [17]. By 9months, PrPSc wasdetected in the myenteric and submucosal plexi throughout thegastrointestinal tract and inthe vagus nerve, and by 16 months, PrPSc deposits were detectable throughoutthe brain andspinal cord. The Prnp genotype seemed to impact the infection kinetics inthat mule deer thatwere SF heterozygous at codon 225 showed a delay in PrPSc spread; PrPSc wasnotdetectable in the brain until 16 months post-inoculation which was 13 monthslater than the225SS deer. Perhaps the 225F allele confers a dominant negative effect onthe kinetics ofthis CWD strain, as has been described in sheep, where the 171R allele hasbeen shown tohave a dominant negative effect on prion susceptibility [20, 33].CWD pathogenesis seems to vary between deer and elk: PrPSc levels have beenfound to belower in lymphoid tissues of elk compared to deer [66]. In a report of 226CWD-infected elk,28 had no PrPSc in lymphoid tissues despite having PrPSc in brain [81].In addition to lymphoid tissues, PrPSc or infectivity has been detected inother non-CNStissues, including pancreas [17, 77], adrenal gland [17, 77], and skeletalmuscle [2]. RecentlyPrPSc was described in cardiac muscle from 7 of 16 (44%) white-tailed deerand from 12 of17 (71%) elk [35]. This is the first report of PrPSc in cardiac muscle inany TSE.The cellular and molecular mechanisms of systemic prion spread are underinvestigation inmany laboratories. A recent report showed that blood from CWD-infected deercontainedinfectivity and could transmit prion disease via a blood transfusion [50].This findingrecapitulates indirect findings of blood infectivity in vCJD affected humans[61] andexperimental transfusion studies of scrapie sick sheep [32], and indicatesthat prion transportthroughout the body may include the blood as a potential vehicle.

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12. Conclusion

CWD in cervids is efficiently transmitted, likely more than any other TSE inanimals orhumans. Therefore, it is unlikely that this TSE can be eradicated, butperhaps through animproved understanding of transmission routes, biological factorsinfluencing pathogenesis,and the molecular basis of CWD prion conversion, a targeted strategy forinterruptingdisease spread may be developed.